Abstract PR007: Physical and metabolic aspects of therapy induced senescence and polyploidy in an evolving tumor microenvironment
Authors: Michelle R. Dawson, Deepraj Ghosh
Journal: Cancer Research (2023)

Abstract Radiation and chemotherapy are highly effective at killing cancer cells but cells that survive treatment often develop therapy-induced senescence (TIS). Since growth is arrested in TIS, this has been considered a positive treatment outcome; however, senescent cells that remain metabolically active and develop a senescence associated secretory phenotype (SASP) can also promote cancer progression. In addition, a small number of cancer cells are able to escape this dormant state and contribute to cancer progression. Polyploid giant cancer cells (PGCCs) represent a small subpopulation of non-mitotic cancer cells that evades treatment through periods of transient dormancy and then relapses into full-blown disease through amitotic budding into chemoresistant progenitor cells. The PGCC phenotype mimics senescent cells in multiple ways, including enlarged size, increased beta-galactosidase expression, increased metabolic activity, and pro-inflammatory SASP; yet, there is a significant gap in our understanding of how PGCCs contribute to TIS escape and subsequent chemoresistance. In addition, increased numbers of large PGCCs are seen in late stage and metastatic cancers; yet, their role in tumor recurrence and metastasis has not been established. We previously showed PGCCs have a unique actin cytoskeletal organization, giving rise to elevated stiffness and migratory persistence. These findings prompted us to further examine vimentin intermediate filaments (VIFs) that act as shock absorbers in the cell, protecting cells from compressive loads. Based on this, we postulated that PGCCs have unique adaptations in their vimentin structure to help support their enlarged morphology and drive their persistent migration. Indeed, we showed that PGCCs have increased levels of cytoplasmic vimentin and evenly distributed VIFs compared to non-PGCCs. This dispersed network of VIFs often polarized at the leading-edge during migration, and was necessary for PGCCs phenotype, as disruption of VIFs decreased PGCC volume and blocked migratory persistence. The VIF network also scaffolds lysosomes and autophagosomes in the cytosol to regulate their fusion during autophagy. Our new data clearly shows that inhibiting autophagy with Bafilomycin limits PGCC migration. In addition, targeting VIF structure also blocks autophagy. Thus, the structure of VIFs and autophagic flux are both critical in directing PGCCs migratory persistence. We have developed a novel 3D tumor microenvironment model that allows us to monitor cancer cell behavior over 4-6 weeks, which allows us to monitor cell recovery from TIS and dormancy. Using this model, we show that PGCC’s unique biophysical properties are directly linked to their dysregulated metabolism and altered cell structure. These studies provide critical information about how aging, TIS, and polyploidy affect evolving tumor microenvironments. Citation Format: Michelle R. Dawson, Deepraj Ghosh. Physical and metabolic aspects of therapy induced senescence and polyploidy in an evolving tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR007.